1. Field of the Invention
The present invention relates to novel processes for producing γ-hydroxyamino acid derivatives, especially monatins. More specifically, it relates to process in which dihydroisoxazole derivatives are converted to γ-hydroxyamino acid derivatives which are important as synthetic intermediates. The present invention more especially relates to processes in which dihydroisoxazole derivatives having an indolyl group are converted to monatins (including stereoisomers, salts thereof, and those with one or more protected functional groups), which are excellent as sweeteners or active ingredients thereof.
2. Discussion of the Background
In recent years, with the higher level of eating habits, obesity due to the excessive intake of sugar in particular and the consequent diseases have become a serious health issue. Accordingly, the development of low-caloric (low-calorie) sweeteners that replace sugar has been in high demand. For these sweeteners, characteristics such as low calorie content, safety, stability to heat or acid, sweetness quality, and costs have to be taken into consideration in addition to the degree of sweetness (sweetening potency).
Various sweeteners have been currently in use or proposed. For example, aspartame is a sweetener with a high degree of sweetness which is capable of industrial mass-production and has actually found wide acceptance. Aspartame is excellent in regard to safety and sweetness quality. Further, aspartame derivatives have been increasingly studied. In addition to aspartame and aspartame derivatives, other sweetening materials having various characteristics as sweeteners have been proposed and studied for actual use. For example, thaumatin, glycyrrhizin, and stevioside derived from plants, which are present in nature and can be collected in large quantities, have been currently used as natural sweeteners.
Monatin is a natural amino acid derivative isolated from the bark of the roots of Schlerochiton ilicifolius, a plant that grows wild in the north-western Transvaal region of South Africa. Monatin has been reported to have a structure which corresponds to (2S,4S)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl)pentanoic acid, or alternatively, (2S,4S)-4-hydroxy-4-(3-indolylmethyl)-glutamic acid; see the structural formula (3) (R. Vleggaar et al., J. Chem. Soc. Perkin Trans., pp. 3095-3098 (1992)).
The degree of sweetness of the (2S,4S) compound derived from the natural plant has been determined to be 800 times or 1,400 times that of sucrose (see, R. Vleggaar et al., J. Chem. Soc. Perkin Trans., pp. 3095-3098 (1992)).
Various processes for producing monatin have been reported (see, P. J. van Wyk et al., ZA 87/4288; C. W. Holzapfel et al., Synthetic Communications, vol. 24(22), pp. 3197-3211 (1994); E. Abushanab et al., U.S. Pat. No. 5,994,559 (1999); and K. Nakamura et al., Organic Letters, vol. 2, pp. 2967-2970 (2000)). However, there is no appropriate industrial process for producing monatin.
In Synthetic Communications, vol. 24(22), pp. 3197-3211 (1994) and U.S. Pat. No. 5,128,482, dihydroisoxazole derivatives represented by the following structural formula (4) are reduced with sodium amalgam (NaHg) to convert the same to monatins represented by the following structural formula (3).
However, since this process uses a mercury compound having a high toxicity, it is extremely dangerous in operation. When the products are used as sweeteners, a procedure for thoroughly removing mercury with an ion exchange resin or the like after completion of the reaction is indispensable. Although U.S. Pat. No. 5,128,482 broadly claims “chemically reducing” a compound of the structural formula (4) to obtain a compound of the structural formula (3), only the use of sodium amalgam is demonstrated in the Examples. Moreover, reagents, reaction conditions and the like are neither specifically claimed nor described in detail. In the description of the chemical reduction step, only sodium amalgam (amalgam reduction), cyanoborohydride (hydride reduction) and sodium (molten metal reduction) are listed as reducing agents. There is no description of catalytic hydrogenation. Moreover, it is known that reduction of an aromatic ring such as an indolyl group proceeds as a side reaction to catalytic hydrogenation. In other words, the hydrogenation reaction for the conversion as described above has not been reported.
The conversion of a diethyl 5-methyl-4,5-dihydroisoxazole-3,5-dicarboxylate (the compound of the general formula (1) in which R1 is a methyl group and R2 and R3 are each an ethyl group) to a γ-hydroxyamino acid derivative has been reported (see, V. Helaine et al., Tetrahedron: Asymmetry, vol. 9, pp. 3855-3861 (1998)).
When the compound is reacted as such, conversion to a lactam occurs and the reaction is therefore conducted in the presence of benzoic anhydride to obtain an N-benzoyl derivative. Thus, although a γ-hydroxyamino acid derivative is obtained by the catalytic hydrogenation reaction of the derivative in which R1 is a methyl group, the reaction solution is heated to reflux overnight in 6 N-hydrochloric acid aqueous solution for removal of the benzoyl group. However, when a functional group extremely labile to an acid, such as an indolylmethyl group is present in a molecule, such severe deprotection conditions cannot be applied. Accordingly, a conversion method that does not require such a procedure is desired.
Thus, there remains a need for a practical and simple process for converting dihydroisoxazole derivatives represented by the structural formula (1) to the γ-hydroxyamino acid derivatives of formula (2).
There also remains a need for a practical and simple process for converting dihydroisoxazole derivatives represented by the structural formula (4) and the like to the monatins represented by the structural formula (3).
